Galantamine for dementia due to Alzheimer's disease and mild cognitive impairment.
Dementia leads to progressive cognitive decline, and represents a significant health and societal burden. Its prevalence is growing, with Alzheimer's disease as the leading cause. There is no cure for Alzheimer's disease, but there are regulatory-approved pharmacological interventions, such as galantamine, for symptomatic relief. This review updates the 2006 version.
To assess the clinical effects, including adverse effects, of galantamine in people with probable or possible Alzheimer's disease or mild cognitive impairment, and to investigate potential moderators of effect.
We systematically searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register on 14 December 2022 using the term 'galantamine'. The Register contains records of clinical trials identified from major electronic databases (including CENTRAL, MEDLINE, and Embase), trial registries, grey literature sources, and conference proceedings. We manually searched reference lists and collected information from US Food and Drug Administration documents and unpublished trial reports. We imposed no language restrictions.
We included double-blind, parallel-group, randomised controlled trials comparing oral galantamine with placebo for a treatment duration exceeding four weeks in people with dementia due to Alzheimer's disease or with mild cognitive impairment.
Working independently, two review authors selected studies for inclusion, assessed their quality, and extracted data. Outcomes of interest included cognitive function, change in global function, activities of daily living, functional disability, behavioural function, and adverse events. We used a fixed-effect model for meta-analytic synthesis, and presented results as Peto odds ratios (OR) or weighted mean differences (MD) with 95% confidence intervals. We used Cochrane's original risk of bias tool (RoB 1) to assess the risk of bias in the included studies.
We included 21 studies with a total of 10,990 participants. The average age of participants was 74 years, and 37% were male. The studies' durations ranged from eight weeks to two years, with 24 weeks being the most common duration. One newly included study assessed the effects of galantamine at two years, and another newly included study involved participants with severe Alzheimer's disease. Nineteen studies with 10,497 participants contributed data to the meta-analysis. All studies had low to unclear risk of bias for randomisation, allocation concealment, and blinding. We judged four studies to be at high risk of bias due to attrition and two due to selective outcome reporting. Galantamine for dementia due to Alzheimer's disease We summarise only the results for galantamine given at 8 to 12 mg twice daily (total galantamine 16 mg to 24 mg/day), assessed at six months. See the full review for results of other dosing regimens and assessment time points. There is high-certainty evidence that, compared to placebo, galantamine improves: cognitive function, as assessed with the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) (MD-2.86, 95% CI -3.29 to -2.43; 6 studies, 3049 participants; minimum clinically important effect (MCID) = 2.6- to 4-point change); functional disability, as assessed with the Disability Assessment for Dementia (DAD) scale (MD 2.12, 95% CI 0.75 to 3.49; 3 studies, 1275 participants); and behavioural function, as assessed with the Neuropsychiatric Inventory (NPI) (MD -1.63, 95% CI -3.07 to -0.20; 2 studies, 1043 participants) at six months. Galantamine may improve global function at six months, as assessed with the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) (OR 1.58, 95% CI 1.36 to 1.84; 6 studies, 3002 participants; low-certainty evidence). Participants who received galantamine were more likely than placebo-treated participants to discontinue prematurely (22.7% versus 17.2%) (OR 1.41, 95% CI 1.19 to 1.68; 6 studies, 3336 participants; high-certainty evidence), and experience nausea (20.9% versus 8.4%) (OR 2.89, 95% CI 2.40 to 3.49; 7 studies, 3616 participants; high-certainty evidence) during the studies. Galantamine reduced death rates at six months: 1.3% of participants in the galantamine groups had died compared to 2.3% in the placebo groups (OR 0.56, 95% CI 0.33 to 0.96; 6 studies, 3493 participants; high-certainty evidence). Galantamine for mild cognitive impairment We summarise results, assessed at two years, from two studies that gave participants galantamine at 8 to 12 mg twice daily (total galantamine 16 mg to 24 mg/day). Compared to placebo, galantamine may not improve cognitive function, as assessed with the expanded ADAS-cog for mild cognitive impairment (MD -0.21, 95% CI -0.78 to 0.37; 2 studies, 1901 participants; low-certainty evidence) or activities of daily living, assessed with the Alzheimer's Disease Cooperative Study - Activities of Daily Living scale for mild cognitive impairment (MD 0.30, 95% CI -0.26 to 0.86; 2 studies, 1901 participants; low-certainty evidence). Participants who received galantamine were probably more likely to discontinue prematurely than placebo-treated participants (40.7% versus 28.6%) (OR 1.71, 95% CI 1.42 to 2.05; 2 studies, 2057 participants) and to experience nausea (29.4% versus 10.7%) (OR 3.49, 95% CI 2.75 to 4.44; 2 studies, 2057 participants), both with moderate-certainty evidence. Galantamine may not reduce death rates at 24 months compared to placebo (0.5% versus 0.1%) (OR 5.03, 95% CI 0.87 to 29.10; 2 studies, 2057 participants; low-certainty evidence). Results from subgroup analysis and meta-regression suggest that an imbalance in discontinuation rates between galantamine and placebo groups, together with the use of the 'last observation carried forward' approach to outcome assessment, may potentially bias cognitive outcomes in favour of galantamine.
Compared to placebo, galantamine (when given at a total dose of 16 mg to 24 mg/day) slows the decline in cognitive function, functional ability, and behaviour at six months in people with dementia due to Alzheimer's disease. Galantamine probably also slows declines in global function at six months. The changes observed in cognition, assessed with the ADAS-cog scale, were clinically meaningful. Gastrointestinal-related adverse events are the primary concerns associated with galantamine use in people with dementia, which may limit its tolerability. Although death rates were generally low, participants in the galantamine groups had a reduced risk of death compared to those in the placebo groups. There is no evidence to support the use of galantamine in people with mild cognitive impairment.
Lim AWY
，Schneider L
，Loy C
《Cochrane Database of Systematic Reviews》
Azathioprine for people with multiple sclerosis.
Multiple sclerosis (MS) is an immune-mediated, chronic, inflammatory demyelinating disease of the central nervous system, impacting around 2.8 million people worldwide. Characterised by recurrent relapses or progression, or both, it represents a substantial global health burden, affecting people, predominantly women, at a young age (the mean age of diagnosis is 32 years). Azathioprine is used to treat chronic inflammatory and autoimmune diseases, and it is used in clinical practice as an off-label intervention for MS, especially where access to on-label disease-modifying treatments (DMTs) for MS is limited. Given this, a review of azathioprine's benefits and harms would be timely and valuable to inform shared healthcare decisions.
To evaluate the benefits and harms of azathioprine (AZA) for relapsing and progressive multiple sclerosis (MS), compared to other disease-modifying treatments (DMTs), placebo or no treatment. Specifically, we will assess the following comparisons. AZA compared with other DMTs or placebo as first-choice treatment for relapsing forms of multiple sclerosis AZA compared with other DMTs or placebo for relapsing forms of MS when switching from another DMT AZA compared with other DMTs or placebo as first-choice treatment for progressive forms of MS AZA compared with other DMTs or placebo for progressive forms of MS when switching from another DMT SEARCH METHODS: We conducted an extensive search for relevant literature using standard Cochrane search methods. The most recent search date was 9 August 2023.
We included randomised controlled trials (RCTs) lasting 12 months or more that compared azathioprine versus DMTs, placebo or no intervention in adults with MS. We considered evidence from non-randomised studies of interventions (NRSIs) as these studies may provide additional evidence not available from RCTS. We excluded cluster-randomised trials, cross-over trials, interrupted time series, case reports and studies of within-group design with no control group.
We followed standard Cochrane methodology. There were three outcomes we considered to be critical: disability, relapse and serious adverse events (SAEs, as defined in the studies). We were also interested in other important outcomes: quality-of-life (QoL) impairment (mental score), short-term adverse events (gastrointestinal disorders), long-term adverse events (neoplasms) and mortality.
We included 14 studies: eight RCTs (1076 participants included in meta-analyses) and six NRSIs (1029 participants). These studies involved people with relapsing and progressive MS. Most studies included more women (57 to 83%) than men, with participants' average age at the onset of MS being between 29.4 and 33.4 years. Five RCTs and all six NRSIs were conducted in Europe (1793 participants); two RCTs were conducted in the USA (126 participants) and one in Iran (94 participants). The RCTs lasted two to three years, while NRSIs looked back up to 10 years. Four studies received some funding or support from commercial interests and five were funded by government or philanthropy; the other five provided no information about funding. There are three ongoing studies. Comparison groups included other DMTs (interferon beta and cyclosporine A), placebo or no treatment. Below, we report on azathioprine as a 'first choice' treatment compared to interferon beta for people with relapsing MS. None of the studies reported on any critical or important outcome for this comparison for progressive MS. No study was retrieved comparing azathioprine to placebo or other DMTs for either relapsing or progressive MS. Furthermore, the NRSIs did not provide information not already covered in the RCTs. Azathioprine as a first-choice treatment compared to other DMTs (specifically, interferon beta) for relapsing MS - The evidence is very uncertain about the effect of azathioprine on the number of people with disability progression over two years compared to interferon beta (risk ratio (RR) 0.19, 95% confidence interval (CI) 0.02 to 1.58; 1 RCT, 148 participants; very low certainty evidence). - Azathioprine may decrease the number of people with relapses over a one- to two-year follow-up compared to interferon beta (RR 0.61, 95% CI 0.43 to 0.86; 2 RCTs, 242 participants; low-certainty evidence). - Azathioprine may result in a possible increase in the number of people with SAEs over two years in comparison with interferon beta (RR 6.64, 95% CI 0.35 to 126.27; 1 RCT, 148 participants; low-certainty evidence). - The evidence is very uncertain about the effect of azathioprine on the number of people with the short-term adverse event of gastrointestinal disorders over two years compared to interferon beta (RR 5.30, 95% CI 0.15 to 185.57; 2 RCTs, 242 participants; very low certainty evidence). We found no evidence comparing azathioprine to other DMTs for QoL impairment (mental score), long-term adverse events (neoplasms) or mortality.
Azathioprine has been proposed as an alternative treatment for MS when access to approved, on-label DMTs is limited, especially in resource-limited settings. The limited evidence available suggests that azathioprine may result in a modest benefit in terms of relapse frequency, with a possible increase in SAEs, when compared to interferon beta-1b, for people with relapsing-remitting multiple sclerosis. The evidence for the effect on disability progression and short-term adverse events is very uncertain. Caution is required in interpreting the conclusions of this review since our certainty in the available evidence on the benefits and harms of azathioprine in multiple sclerosis is low to very low, implying that further evidence is likely to change our conclusions. An important limitation we noted in the available evidence is the lack of long-term comparison with other treatments and the failure of most studies to measure outcomes that are important to people with multiple sclerosis, such as quality of life and cognitive decline. This is especially the case in the evidence relevant to people with progressive forms of multiple sclerosis.
Ridley B
，Nonino F
，Baldin E
，Casetta I
，Iuliano G
，Filippini G
... -
《Cochrane Database of Systematic Reviews》
Interleukin-6 blocking agents for treating COVID-19: a living systematic review.
Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance.
To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly.
We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021.
We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity.
We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events.
We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes.
On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).
Ghosn L
，Chaimani A
，Evrenoglou T
，Davidson M
，Graña C
，Schmucker C
，Bollig C
，Henschke N
，Sguassero Y
，Nejstgaard CH
，Menon S
，Nguyen TV
，Ferrand G
，Kapp P
，Riveros C
，Ávila C
，Devane D
，Meerpohl JJ
，Rada G
，Hróbjartsson A
，Grasselli G
，Tovey D
，Ravaud P
，Boutron I
... -
《Cochrane Database of Systematic Reviews》
ResearchGate
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